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Biochimica Et Biophysica Acta.... May 2019Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It... (Review)
Review
Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clinical testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a critical review of the most popular animal models of DILI, and to discuss the future of DILI research.
Topics: Acetaminophen; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Humans; Immune Tolerance
PubMed: 31007174
DOI: 10.1016/j.bbadis.2018.08.037 -
Scientific Reports Mar 2023Hepatic fibrosis is a late stage process of many chronic liver diseases. Blocking the fibrosis process will be beneficial to the treatment and recovery of the diseases....
Hepatic fibrosis is a late stage process of many chronic liver diseases. Blocking the fibrosis process will be beneficial to the treatment and recovery of the diseases. Mangiferin has many pharmacological activities. Recently, it has been reported that mangiferin may relieve tissue fibrosis, including renal, myocardial, pulmonary fibrosis via anti-inflammatory and anti-oxidative effects in animal models. Here, we investigate the effects of mangiferin on CCl4-induced liver fibrosis and the underlying mechanism in mice. Thirty-two male C57BL/6 mice were randomly divided into 4 groups (n = 8 in each group), injected with carbon tetrachloride (10% CCl4) for 8 weeks, and oral administrated with mangiferin (50 mg/kg or 100 mg/kg) from the fifth week. The serum levels of ALT, AST were analyzed to evaluate liver function. H&E, Masson's trichrome and Sirius red staining were used to assess liver morphology and the degree of liver fibrosis. Quantitative RT-PCR and Western blot were used to assay the gene expression and protein levels. The results showed that mangiferin alleviated the serum levels of AST, ALT, ALP, TBA and TBIL, reduced liver lesions, prevented hepatic parenchymal necrosis, and ameliorated collagen accumulation in the liver of CCl4-treated mice. Meanwhile, mangiferin inhibited the expression of inflammatory genes IL-6 and IL-1β, fibrogenic genes α-SMA, TGF-β and MMP-2 and bile acid metabolism genes ABCB4, ABCB11, SULT2A1 in the liver of CCl4-treated mice. Furthermore, mangiferin reduced collagen accumulation and HSCs activation, inhibited the p-IκB and p-p65 protein levels. Our results suggest that mangiferin could alleviate liver fibrosis in CCl4-treated mice through inhibiting NF-κB signaling, and mango consuming may have beneficial effects to hepatic fibrosis.
Topics: Mice; Male; Animals; Mice, Inbred C57BL; Liver Cirrhosis; Liver; Fibrosis; Carbon Tetrachloride; Collagen
PubMed: 36914687
DOI: 10.1038/s41598-023-30582-3 -
Hepatology (Baltimore, Md.) Nov 2021HSCs and portal fibroblasts (PFs) are the major sources of collagen-producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the...
BACKGROUND AND AIMS
HSCs and portal fibroblasts (PFs) are the major sources of collagen-producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the mechanisms by which their dynamic gene expression directs the transition from the quiescent to the activated state-as well as their contributions to fibrotic myofibroblasts-remain unclear. Here, we analyze the activation of HSCs and PFs in CCL -induced and bile duct ligation-induced fibrosis mouse models, using single-cell RNA sequencing and lineage tracing.
APPROACH AND RESULTS
We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix-producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL -treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single-cell and lineage-tracing analysis also uncovers differential gene-expression features between HSCs and PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed in HSCs, but not in PFs. The soluble guanylate cyclase stimulator Riociguat potently reduced liver fibrosis in CCL -treated livers but showed no therapeutic efficacy in bile duct ligation livers.
CONCLUSIONS
This study provides a transcriptional roadmap for the activation of HSCs during liver fibrosis and yields comprehensive evidence that the differential transcriptomic features of HSCs and PFs, along with their relative contributions to liver fibrosis of different etiologies, should be considered in developing effective antifibrotic therapeutic strategies.
Topics: Animals; Carbon Tetrachloride; Cell Lineage; Cells, Cultured; Gene Expression Regulation; Gene Knock-In Techniques; Hepatic Stellate Cells; Humans; Liver Cirrhosis, Experimental; Male; Mice; Mice, Transgenic; Myofibroblasts; Primary Cell Culture; RNA-Seq; Single-Cell Analysis
PubMed: 34089528
DOI: 10.1002/hep.31987 -
BMC Medicine Sep 2022Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC)...
BACKGROUND
Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSEC still remains unclear.
METHODS
The expression level of lncRNA Airn was evaluated in both human fibrotic livers and serums, as well as mouse fibrotic livers. Gain- and loss-of-function experiments were performed to detect the effect of Airn on LSEC differentiation and hepatic stellate cell (HSC) activation in liver fibrosis. Furthermore, RIP, RNA pull-down-immunoblotting, and ChIP experiments were performed to explore the underlying mechanisms of Airn.
RESULTS
We have identified Airn was significantly upregulated in liver tissues and LSEC of carbon tetrachloride (CCl)-induced liver fibrosis mouse model. Moreover, the expression of AIRN in fibrotic human liver tissues and serums was remarkably increased compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl- and bile duct ligation (BDL)-induced liver fibrosis, while Airn over-expression by AAV8 alleviated CCl-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSEC differentiation in vivo and in vitro. Additionally, Airn inhibited HSC activation indirectly by regulating LSEC differentiation and promoted hepatocyte (HC) proliferation by increasing paracrine secretion of Wnt2a and HGF from LSEC. Mechanistically, Airn interacted with EZH2 to maintain LSEC differentiation through KLF2-eNOS-sGC pathway, thereby maintaining HSC quiescence and promoting HC proliferation.
CONCLUSIONS
Our work identified that Airn is beneficial to liver fibrosis by maintaining LSEC differentiation and might be a serum biomarker for liver fibrogenesis.
Topics: Animals; Biomarkers; Carbon Tetrachloride; Endothelial Cells; Humans; Kruppel-Like Transcription Factors; Liver; Liver Cirrhosis; Mice; RNA, Long Noncoding
PubMed: 36171606
DOI: 10.1186/s12916-022-02523-w -
Cellular and Molecular Gastroenterology... 2023Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP...
BACKGROUND & AIMS
Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro.
METHODS
FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics.
RESULTS
FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP.
CONCLUSIONS
Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.
Topics: Humans; Mice; Animals; Carbon Tetrachloride; Liver Cirrhosis; Liver Diseases; Inflammation; Fibrosis; Hepatitis; Collagen; Fibroblasts; Macrophages
PubMed: 36521660
DOI: 10.1016/j.jcmgh.2022.12.005 -
Pharmacological Research Mar 2023The roles of nuclear receptor subfamily 1 group d member 1 (NR1D1) and the circadian clock in liver fibrosis remain unclear. Here, we showed that liver clock genes,...
The roles of nuclear receptor subfamily 1 group d member 1 (NR1D1) and the circadian clock in liver fibrosis remain unclear. Here, we showed that liver clock genes, especially NR1D1, were dysregulated in mice with carbon tetrachloride (CCl)-induced liver fibrosis. In turn, disruption of the circadian clock exacerbated experimental liver fibrosis. NR1D1-deficient mice were more sensitive to CCl-induced liver fibrosis, supporting a critical role of NR1D1 in liver fibrosis development. Validation at the tissue and cellular levels showed that NR1D1 was primarily degraded by N6-methyladenosine (mA) methylation in a CCl-induced liver fibrosis model, and this result was also validated in rhythm-disordered mouse models. In addition, the degradation of NR1D1 further inhibited the phosphorylation of dynein-related protein 1-serine site 616 (DRP1), resulting in weakened mitochondrial fission function and increased mitochondrial DNA (mtDNA) release in hepatic stellate cell (HSC), which in turn activated the cGMP-AMP synthase (cGAS) pathway. Activation of the cGAS pathway induced a local inflammatory microenvironment that further stimulated liver fibrosis progression. Interestingly, in the NR1D1 overexpression model, we observed that DRP1 phosphorylation was restored, and cGAS pathway was also inhibited in HSCs, resulting in improved liver fibrosis. Taken together, our results suggest that targeting NR1D1 may be an effective approach to liver fibrosis prevention and management.
Topics: Mice; Animals; Hepatic Stellate Cells; Circadian Clocks; Methylation; Liver Cirrhosis; Liver; Nucleotidyltransferases; Carbon Tetrachloride; Nuclear Receptor Subfamily 1, Group D, Member 1
PubMed: 36813093
DOI: 10.1016/j.phrs.2023.106704 -
IARC Monographs on the Evaluation of... 1999
Review
Topics: Animals; Carbon Tetrachloride; Carcinogenicity Tests; Carcinogens; Humans; Mutagenicity Tests; Mutagens; Neoplasms; Neoplasms, Experimental; Occupational Exposure
PubMed: 10476455
DOI: No ID Found -
Ecotoxicology and Environmental Safety Sep 2022Carbon tetrachloride (CCL) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL is highly toxic in the liver,...
Carbon tetrachloride (CCL) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL on ovarian function has not been reported. In this study, we found that the mice treated with CCL showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17β-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1β, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL group. In the CCL treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.
Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytokines; Fibrosis; Liver; Mice; Oxidative Stress
PubMed: 35816842
DOI: 10.1016/j.ecoenv.2022.113859 -
Croatian Medical Journal Aug 2023To evaluate the effect of lycopene on carbon tetrachloride (CCl4)-induced hepatic fibrosis and elucidate the underlying mechanism.
AIM
To evaluate the effect of lycopene on carbon tetrachloride (CCl4)-induced hepatic fibrosis and elucidate the underlying mechanism.
METHODS
Male rats were randomly assigned to the control group, CCl4 group, and lycopene group. The CCl4 group was intraperitoneally injected with CCl4 twice per week for 12 weeks to induce hepatic fibrosis. The control group was intraperitoneally injected with olive oil. Lycopene was orally administered during CCl4 treatment. Body weight and liver weight were recorded. Liver function was assessed. Biomarkers of oxidative stress and inflammatory factors were measured. Histological changes and collagen expression were evaluated. The expression of TGF-β1, α-SMA, HO-1, SIRT 1, REDD1, SHP2, P62, and LC3 in the liver was determined, as well as the levels of phosphorylated NF-κB and IκB α.
RESULTS
Lycopene significantly reduced the liver/body weight ratio, and AST (P=0.001) and ALT levels (P=0.009). It also significantly increased CAT and SOD activities (P<0.001) and decreased MDA content (P<0.001), IL-6 (P<0.001), and TNF-α (P=0.001). Histological analysis demonstrated that lycopene improved lobular architecture and decreased collagen expression. It also decreased the expression of TGF-β1, α-SMA, P62, and SHP2, and increased the ratio of LC3 II/I, as well as Beclin 1 and REDD1 expression. In addition, it reduced NF-κB and IκB-α phosphorylation, and elevated the levels of HO-1, SIRT 1, and PGC 1α.
CONCLUSION
Lycopene attenuates CCl4-induced hepatic fibrosis because of its effect on autophagy by reducing oxidative stress and inflammation.
Topics: Male; Animals; Rats; Carbon Tetrachloride; Lycopene; Transforming Growth Factor beta1; NF-kappa B; Liver Cirrhosis; Autophagy; Body Weight
PubMed: 37654036
DOI: 10.3325/cmj.2023.64.243 -
Environmental Health Perspectives Dec 1974A review of fibrogenesis by asbestos fibers is given. There is nothing to indicate that the fibrogenic effects of inhaled asbestos fibers should differ in any way from... (Review)
Review
A review of fibrogenesis by asbestos fibers is given. There is nothing to indicate that the fibrogenic effects of inhaled asbestos fibers should differ in any way from those of ingested asbestos. Recently, ingestion has assumed some importance concerning human exposure. Three sections dealing with the process of fibrogenesis are covered: the first deals with in vitro fibrogenesis, in particular the interrelation of macrophages damaged by dusts and the subsequent laying down of collagen by fibroblasts in culture; the second deals with in vivo fibrogenesis after the inoculation of extracts of silica-treated macrophages into various animals, and the third, with the fibrogenicity of a wide variety of mineral fibers in man and experimental animals. Recent studies described in the first section of the present review appear to offer a better understanding of the effects of macrophages on fibroblasts after tissue damage of various kinds has occurred.
Topics: Animals; Asbestos; Carbon Tetrachloride; Collagen; Cricetinae; Culture Techniques; Dust; Fibroblasts; Guinea Pigs; Humans; Macrophages; Mice; Quartz; Rats; Silicon Dioxide
PubMed: 4377874
DOI: 10.1289/ehp.749271